The present invention relates generally to methods for mobilizing hematopoietic stem cells and to a novel deamidated chemokine.
All the members of the intercrine or chemokine family are basic heparin-binding polypeptides which have four cysteine residues which form two disulfide bridges. All these proteins which have been functionally characterized appear to be involved in proinflammatory and/or restorative functions.
In clinical situations for the use of high dose chemotherapy, the biomolecule of choice has been G-CSF. Generally, in such treatment, patients are primed with a low dose of a chemotherapeutic agent like cyclophosphamide. During the remission, the patient is treated with a CSF, such as G-CSF, which causes eventual mobilization of cells from the bone marrow to the peripheral circulation for harvesting of leukophoresed blood. The patient is thereafter administered a high dose of chemotherapy to induce clinical remission of their cancer. The resultant bone marrow failure is treated by infusion of the stored blood cells collected previously. This procedure may be modified, e.g., by the omission of the initial dose of chemotherapy and/or alternate blood collection protocols.
While the use of these hematopoietic stem cell transplantation techniques looks promising, multiple apheresis procedures are required to harvest sufficient stem cells for successful engraftment to treat severe myelosuppression when G-CSF is used alone [see, e.g., Bensinger et al, Blood, 81:3158 (1993) and R. Haas et al, Sem. in Oncology, 21:19 (1994)]. Thus, despite these significant advances and the availability of certain regulatory biomolecules, delayed recovery of hematopoiesis remains an important source of morbidity and mortality for myelosuppressed patients.
There exists a continuing need in the art for compositions and methods to enhance hematopoietic recovery, particularly in cases of chemotherapy associated myelosuppression.
In one aspect, the present invention provides for the use of a chemokine in the preparation of a medicament for the stimulation of hematopoietic stem cells. This chemokine includes proteins derived from KC, groxcex2, groxcex1, and groxcex3, including mature, modified, and multimeric forms of these chemokines.
In yet a further aspect, the present invention provides a method for mobilizing hematopoietic stem cells in an animal comprising administering to an animal an effective amount of a mature or modified or multimeric chemokine as described herein.
In a further aspect, the present invention provides a novel deamidated form of a modified groxcex2 (amino acids 5-73 of SEQ ID NO: 3) which is useful for mobilizing hematopoietic stem cells.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
FIG. 1 is a graph demonstrating the effect of groxcex2 (amino acids 1-73 of SEQ ID NO: 3) in the single agent mobilization assay of Example 1.
FIG. 2 is a graph demonstrating the effect of modified groxcex2 (amino acids 5-73 of SEQ ID NO: 3) in the single agent mobilization assay of Example 1.
FIG. 3 is a bar graph demonstrating the comparison of phosphate buffered saline (PBS), IL-8, groxcex2 (amino acids 1-73; SEQ ID NO: 3) and modified groxcex2 (amino acids 5-73 of SEQ ID NO: 3) in the single agent mobilization assay.